Analytical Validation Methods in Good Manufacturing Practice
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Explore the importance of analytical monitoring and validation in GMP, covering protocol development, instrument qualification, and validation characteristics. Learn about analytical procedures, methods transfer, and statistical analysis.
Analytical Validation Methods in Good Manufacturing Practice
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Presentation Transcript
Validation Part 4:QC-related validation Supplementary Training Modules on Good Manufacturing Practice
Validation Introduction • Why is analytical monitoring necessary? • What is the purpose of analytical validation?
Validation Objectives To introduce the concepts of : • Protocol development • Instrument qualification • Analytical procedure • Extent of validation • Method transfer • Chemical and physical, biological, and microbiological test validation
Validation Validation of analytical procedures requires: • Qualified and calibrated instruments • Documented methods • Reliable reference standards • Qualified analysts • Sample integrity
Validation Validation protocol for analytical method • Statement of purpose and scope • Responsibilities • Documented test method • List of materials and equipment • Procedure for the experiments for each parameter • Statistical analysis • Acceptance criteria for each performance parameter
Validation Qualification of the instrument • Make, model and maker’s manual • Modifications • Installation and operational qualification • Calibration programs • Maintenance schedules
Validation Characteristics of analytical procedures (1) • Accuracy • Precision • Repeatability • Reproducibility
Validation Relationship between accuracy and precision Accurate AND Precise
Validation Characteristics of analytical procedures (2) • Ruggedness • Robustness • Variability caused by: • Day-to-day variations • Analyst-to-analyst • Laboratory-to-laboratory • Instrument-to-instrument • Chromatographic column-to-column • Reagent kit-to-kit • Instability of analytical reagents
Validation Characteristics of analytical procedures (3) • Linearity and range • Specificity • Sensitivity • Limit of detection • Limit of quantitation
Table of values (x,y) x y # Reference material mg/ml Calculated mg/ml 1 0.0100 0.0101 2 0.0150 0.0145 3 0.0200 0.0210 4 0.0250 0.0260 5 0.0300 0.0294 6 0.0400 0.0410 Validation
Validation Linearity Statistics • Intercept -0.0002 • Limit of Linearity and Range 0.005 – 0.040 mg/mL • Slope 1.0237 • Correlation coefficient • Pearson 0.9978 • Olkin and Pratt 0.9985 • Relative procedure standard deviation 3.4%
Validation LOQ, LOD and SNR • Limit of Quantitation • Limit of Detection • Signal to Noise Ratio Peak BLOQ Peak ALOD noise Baseline
Validation Different classes of analytical tests • Class A: To establish identity • Class B: To detect and quantitate impurities • Class C: To determine quantitatively the concentration • Class D: To assess the characteristics
Characteristic A B quant. B Limit test C D Accuracy X X X* Precision X X X Robustness X X X X X Linearity and range X X X Specificity X X X X X Limit of detection X Limit of quantitation X Validation * A degree of bias may be allowed
Validation Extent of validation • New methods require complete validation • Pharmacopoeial methods require partial validation (or verification) • Significant changes mean partial revalidation • equipment changes • formula changed • changed suppliers of critical reagents
Validation Analytical method transfer • Method transfer protocol and procedure • precision • accuracy • ruggedness • Written and approved specific test method • Proficiency check • Formal acceptance by new laboratory
Validation Chemical laboratory validation requirements (1) • Balances • Chromatography • HPLC, HPTLC, GC, TLC • Dissolution or disintegration apparatus • Karl Fischer moisture determination • Melting, softening or freezing point apparatus • Ovens, refrigerators, incubators
Validation Chemical laboratory validation requirements (2) • pH meter • Polarimeter - optical rotation • Refractometer • Spectrophotometer UV/Vis, IR, FTIR, Raman, AA • Timers • Viscometer • Volumetric equipment
Validation Typical validation of HPCL assay (1) • System suitability (performance check) • system precision • column efficiency • symmetry factor • capacity factor
Validation Typical validation of HPLC assay (2) • Method validation • specificity • accuracy • precision • linearity • robustness
Validation Biological assays • Can be difficult to "validate" • "Validity" on a case by case basis • Strictly adhere to the Biological Testing monographs in pharmacopoeias
Validation Microbiological testing requiring validation • Microbial limit testing • Microbial count • Sterility testing • Preservative effectiveness testing • Environmental monitoring program • Biological testing
Validation Validation of microbial test procedures (1) • Virtually impossible to completely validate test procedures for every microorganism • Neutralize /inactivate inhibitory substances, or dilute • Periodic media challenge • Media QC • Reliable methods
Validation Validation of microbial test procedures (2) • Incubation temperature and time • Media may not grow all microorganisms • Variations in media may affect recovery • Inhibitory disinfectants or preservatives • Sample • procedures • handling, storage, transport
Validation Microbiological viable count method validation (1) • Methods • pour plate / spread plate • membrane filtration • Most Probable Number • Sample size • Test dilution • Inoculation size
Validation Microbiological viable count method validation (2) • Membrane filtration conditions • Incubation conditions • Acceptance criteria
Validation Sterility testing validation requirements • Media growth promotion, sterility, pH • Product validation • Stasis testing • Environmental monitoring • Negative controls • Challenge organisms
